Morphometry and network-based atrophy patterns in SCN1A-related Dravet syndrome

Abstract

Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable phenotypes, from the milder genetic epilepsy with febrile seizures plus to Dravet syndrome, a severe developmental and epileptic encephalopathy. Qualitative neuroimaging studies have identified malformations of cortical development in some patients and mild atrophic changes, partially confirmed by quantitative studies. Precise correlations between MRI findings and clinical variables have not been addressed. We used morphometric methods and network-based models to detect abnormal brain structural patterns in 34 patients with SCN1A-related epilepsy, including 22 with Dravet syndrome. By measuring the morphometric characteristics of the cortical mantle and volume of subcortical structures, we found bilateral atrophic changes in the hippocampus, amygdala, and the temporo-limbic cortex (P-value < 0.05). By correlating atrophic patterns with brain connectivity profiles, we found the region of the hippocampal formation as the epicenter of the structural changes. We also observed that Dravet syndrome was associated with more severe atrophy patterns with respect to the genetic epilepsy with febrile seizures plus phenotype (r = -0.0613, P-value = 0.03), thus suggesting that both the underlying mutation and seizure severity contribute to determine atrophic changes.

Keywords: Dravet syndrome; SCN1A mutation; epilepsy; hippocampus; limbic formation.

Fig. 1

Statistical whole-brain group analysis of SCN1A-patients compared with matched controls. The results of the statistical analysis on CT a) and SA b) are represented by z-value maps superimposed on the pial surfaces of left and right hemispheres. We observed statistically significant lower values of CT and SA in left and right temporo-limbic cortices, and higher but not significant values of CT in orbitofrontal, superior frontal, and occipital cortices (for further details, please see the results of the ROI analysis reported in Table 1).

Fig. 2

Epicenter mapping of CT. Spatial correlations between CT patterns and seed-based cortico-cortical a, b) and subcortico-cortical c, d), structural a, c, blue-black colormap), and functional b, d, red-black colormap) connectivity profiles. In this example, we use as seeds the left entorhinal gyrus a, b) and the left hippocampus c, d).

Fig. 3

Epicenter mapping of SA. Spatial correlations between SA patterns and seed-based cortico-cortical a, b) and subcortico-cortical c, d), structural a, c, blue-black colormap), and functional b, d, red-black colormap) connectivity profiles. In this example, we use as seeds the left entorhinal gyrus a, b) and the left hippocampus c, d).